PROJECT SUMMARY (30-line limit) Deadly diseases such as chronic obstructive pulmonary disease (COPD), asthma, lung injury, constrictive bronchiolitis, and pulmonary fibrosis affect >300 million people worldwide and cause ~3 million annual deaths. However, there is currently no widespread clinical imaging modality to perform high-resolution functional lung imaging: Computed Tomography (CT), conventional MRI, and X-ray can only provide structural images of dense tissues?informing about pathologies like tumors and pneumonia?but yielding little or no information about lung ventilation, perfusion, alveoli size, gas-exchange efficiency, etc. This state of affairs contrasts with cancer imaging, which includes MRI, CT, ultrasound, mammography, Positron Emission Tomography (PET) and others, which collectively enable early detection (via population screening), diagnoses, and monitoring response to treatment. MRI of hyperpolarized noble gases (129Xe and 3He) reports on lung function: ventilation, diffusion, and gas exchange. Despite remarkable research breakthroughs in this field demonstrating the effectiveness and safety of hyperpolarized noble gas MRI to detect a wide range of lung diseases and monitor response to treatment (over the past 20+ years of studies), the prospects for widespread clinical adaptation of this imaging modality face major challenges, including (i) the high cost and complexity of the equipment for production of hyperpolarized noble gases, and (ii) the requirement for a highly specialized custom MRI scanner capable of 129Xe or 3He imaging ? note, all FDA-approved clinical MRI scanners can image only protons. We have been developing a new technology of Parahydrogen Induced Polarization (PHIP) for production of pure proton- hyperpolarized hydrocarbon gases via pairwise parahydrogen addition to an unsaturated precursor (e.g., vinyl ether proposed here). This high-throughput technology is remarkably simple and low-cost. Most importantly, it can be deployed on FDA-approved MRI scanners without any additional of hardware and software upgrades. Here we propose applying this technology for production of diethyl ether, which has a rich history of use as the first inhalable anesthetic, which has revolutionized the field of medicine. Specifically, we propose to develop and optimize the process of clinical-scale production of a human dose of less than 100 mL of gas. Once inhaled, this low dose diethyl ether will render in vivo concentration, which is no longer is flammable. Therefore, we envision the use of low-dose proton-hyperpolarized diethyl ether as a safe MRI contrast agent. We will also perform detailed mapping of relaxation properties of this novel HP contrast agents, and will perform feasibility imaging studies in phantoms and excised animal lungs. We envision that this new safe inhalable contrast agent can revolutionize pulmonary imaging and pulmonary medicine in general.